Multipoint dissolution specification and acceptance sampling rule based on profile modeling and principal component analysis.

In dissolution testing, multiple dissolution measurements at specific time points are needed in quality control when the compliance of the product requires controlled dissolution throughout the time course. The dissolution specification based on general multivariate confidence region was proposed by Chen and Tsong (8). This paper presents two alternative procedures when the dissolution profile consists of important measurements at more than 4 time points. In the first procedure, when the dissolution profile can be described by a physical curve through modeling, the dissolution specification is developed based on the confidence region of the parameters of the physical curve. In the second procedure, the principal components (PCS) as the linear combinations of the dissolution measurements are identified and dissolution specification is set based by the confidence intervals of the values of principal components. In both approaches the specification can be set at lower dimensions than the general multivariate confidence region approach. A single-stage acceptance rule can be used in both approaches by first projecting the dissolution values of each tablet in the new testing batch onto the determined parameters axes (through modeling in modeling approach and through projection on the selected PCS in principal component approach). Then check if the projections of the new tablet fall within the specifications. Finally, count the number of tablets that fall outside the specification limits and reject the batch if the proportion of out-of-specification tablet is high and accept the lot for release if the proportion is low.

High-dose pancreatic-enzyme supplements and fibrosing colonopathy in children with cystic fibrosis.

BACKGROUND: Fibrosing colonopathy has been reported in young children with cystic fibrosis, the majority of whom take high-strength pancreatic-enzyme supplements to control intestinal malabsorption. We conducted a case-control study in the United States to investigate the relation between dose and type of pancreatic-enzyme supplement and fibrosing colonopathy. METHODS: Children with histopathologically confirmed cases of fibrosing colonopathy who required colectomy for colonic strictures from January 1, 1990, through December 31, 1994, were identified. Each of these patients was matched according to age at the time of surgery and medical center with up to four controls with cystic fibrosis who did not have fibrosing colonopathy. RESULTS: We studied 29 patients (mean age, 5.0 years) with fibrosing colonopathy (case patients) and 105 controls (mean age, 5.2 years). The mean dose of pancreatic-enzyme supplement was 50,046 units of lipase per kilogram of body weight per day for the case patients and 18,985 units per kilogram per day for the controls. A history of gastrointestinal complications attributed to cystic fibrosis and the use of histamine H2-receptor blockers, corticosteroids, or recombinant human DNase (dornase alfa) were associated with a higher incidence of fibrosing colonopathy. After adjustment for a history of such complications and the use of these medicines, the relative risk of fibrosing colonopathy that was associated with a dose of 24,001 to 50,000 units of lipase per kilogram per day, as compared with a dose of 0 to 24,000 units per kilogram per day, was 10.9 (95 percent confidence interval, 1.6 to 71.8), and that associated with a dose of more than 50,000 units per kilogram per day was 199.5 (95 percent confidence interval, 9.9 to 4026.0). The strength, coating, and manufacturer of the products used were not associated with the risk of fibrosing colonopathy. CONCLUSIONS: In young children with cystic fibrosis, we found a strong relation between high daily doses of pancreatic-enzyme supplements and the development of fibrosing colonopathy. Our findings support recommendations that the daily dose of pancreatic enzymes for most patients should remain below 10,000 units of lipase per kilogram.

Angiotensin converting enzyme inhibitor-associated angioedema: higher risk in blacks than whites.

We compared the incidence of angioedema during exposure to angiotensin converting enzyme inhibitors (ACEIs) in blacks with that in whites in a retrospective cohort study of Medicaid recipients from Michigan, Ohio and Tennessee during 1986- 1992. Medicaid administrative files were used to identify filled prescriptions for ACEIs and calcium channel blockers (CCBs), and to identify first episodes of angioedema that occurred during exposure to an ACEI or CCB. There were 48,776 black and 106,482 white patients with 43,989 and 114,448 person-years of exposure to an ACEI, respectively. For comparison, there were 49,004 black and 110,129 white patients with 43,064 and 117,684 person-years of exposure to a CCB, respectively. The incidence of angioedema in blacks ranged from 3.3 to 4.6 per 1000 person-years of ACEI exposure--three to four times higher than that for whites in each state. Controlling for a slightly greater incidence of angioedema in blacks and other covariates, black users of ACEIs had a 3.1-fold greater incidence than white users. First exposure to ACEIs was associated with a higher risk of angioedema than chronic exposure in blacks, but not whites. Among blacks, the rate of angioedema during the first 30 days of exposure was 11.4 times greater (95% confidence interval [CI], 3.5 to 37.0) among ACEI users than CCB users; for those with at least 1 year of exposure, the rate was 4.5 times higher (95% CI, 2.6 to 8.0). Among whites, the increased risk of angioedema was more modest (rate ratio 1.7, 95% CI, 1.3 to 2.4 compared to CCB users) and did not differ by duration of ACEI use. In an analysis of angioedema cases and randomly selected controls in a subset of the full cohort, the greater risk of ACEI-associated angioedema in blacks was not explained by concurrent exposure to diuretics or antibiotics. Blacks may be at greater risk of angioedema when taking ACEIs than whites. Further study is necessary to confirm these findings, to examine effects of underlying disease on angioedema incidence, and to describe any racial differences in the severity of angioedema occurring with ACEIs.

Sedative-hypnotic drugs and the risk of hip fracture.

A retrospective cohort study was conducted in individuals 65 years of age and older using Medicaid-reimbursed claims to assess the risk of hip fracture in users of two sedative-hypnotic drugs, triazolam and temazepam. Using the triazolam cohort as the referent group, the rate ratio was 0.92 (95% confidence interval, 0.72 to 1.17) for hip fracture with temazepam. Stratifying by age, sex, race, residence, time enrolled in Medicaid, prescription number, combinations of these, and several other potential confounding variables did not materially change the results. Compared with the short-acting benzodiazepine hypnotic temazepam, use of triazolam, an ultra-short-acting benzodiazepine hypnotic, did not decrease the risk of hip fracture. This study did not determine that either drug, compared with no use in an insomniac control group, increases the risk of hip fracture. However, because sedative-hypnotic drugs have been found in other studies to increase the risk of falling and hip fracture, they should be used with caution, especially in the elderly.

Dissolution test acceptance sampling plans.

The U.S. Pharmacopeia (USP) general monograph provides a standard for dissolution compliance with the requirements as stated in the individual USP monograph for a tablet or capsule dosage form. The acceptance rules recommended by USP have important roles in the quality control process. The USP rules and their modifications are often used as an industrial lot release sampling plan, where a lot is accepted when the tablets or capsules sampled are accepted as proof of compliance with the requirement. In this paper, the operating characteristics of the USP acceptance rules are reviewed and compared to a selected modification. The operating characteristics curves show that the USP acceptance rules are sensitive to the true mean dissolution and do not reject a lot or batch that has a large percentage of tablets that dissolve with less than the dissolution specification.

Temporal patterns in air pollution and hospital admissions.

A 6-year data set of daily counts of admissions to 79 acute care hospitals in Southern Ontario was analyzed in relation to concurrent measurements of air pollution and weather pooled over the same regions, using progressively more sophisticated statistical techniques. The diagnoses studied included a group of respiratory causes and two control diagnoses: accidents and gastrointestinal causes. The 6-year period (1979-1985) was subdivided into six 2-month "seasons" and the area of study was divided into three subregions. Bivariate correlations were found to be significant more often than expected due to chance for all three admissions variables, but accounting for the temporal variation within the 60-day seasons greatly reduced the significance of the control diagnoses. Twenty-four-hour averages for air quality were found to yield more significant associations than peak hourly concentrations. July-August was the only period not having important within-season temporal trends and also had the lowest daily counts for respiratory admissions. Based on a model which accounted for serial correlation, SO2, ozone, and sulfate aerosol were found to be significant predictors of respiratory admissions during July-August. Using cumulative lags increased the magnitude of the estimated response to about 20% of summer respiratory admissions, but no consistent relationships were found which could identify the "responsible" pollutant(s) with certainty. Average pollutant concentrations were generally within U.S. ambient standards.

Health risks of short-term SO2 exposure to exercising asthmatics.

A method is described for quantifying health risks to asthmatics briefly exposed to elevated levels of SO2. By combining symptomological and physiological measurements, we have developed a dose-response surface that relates both severity and incidence of response to ambient air quality levels. The complete model to assess potentially avoidable risks includes power plant emission data; ambient SO2 background levels; demographic and activity patterns of asthmatics, the identified population at risk; and the dose-response surface. The estimated annual risk to persons experiencing an SO2-induced response due to a nearby power plant is quite small (response rates under 3 percent). Uncertainties due to modeling errors, variations in activity patterns, demographics and physiological response are discussed.